P1098: A PHASE II, OPEN-LABEL, MULTICENTER STUDY OF CAPIVASERTIB, A POTENT, ORAL PAN-AKT INHIBITOR, IN PATIENTS WITH RELAPSED OR REFRACTORY B-CELL NON-HODGKIN LYMPHOMA (CAPITAL)
Authors: Daniel Hodson, Geoffrey Shouse, Ho-Jin Shin, Antonio Salar Silvestre, Sabela Bobillo Varela, Vincent Ribrag, Nicol Macpherson, Raul Cordoba, Jin Seok Kim, John Radford, Stephanie Guidez, Alex F. Herrera, Franck Morschhauser, Dachelle Johnson, Macarena Izuzquiza, Nisha Sambamurthy, Alessandra Forcina, Gullu Gorgun, Robert Chen, Anas Younes, Michael Wang, Wong Seog Kim
Journal: HemaSphere (2023)

Topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical Background: The PI3K/AKT/mTOR pathway is an established therapeutic target in indolent B-cell non-Hodgkin lymphoma (B-NHL). Several PI3K inhibitors (PI3Ki) have been approved to treat relapsed/refractory (R/R) follicular lymphoma (FL) and marginal zone lymphoma (MZL). Nonetheless, potential class-specific and PI3K isoform-related toxicities may limit their clinical utility. Capivasertib is an oral, potent, selective pan-AKT inhibitor that has demonstrated evidence of survival benefit in phase 2 clinical studies in patients with solid tumors. Capivasertib has also shown a manageable safety profile and unlike PI3Ki, colitis or pneumonitis do not feature as noted toxicities. Aims: Here, we report preliminary safety and efficacy data from a phase II study evaluating capivasertib in pts with R/R B-NHL (NCT05008055). Methods: Eligible pts were adults (≥18 years) with R/R NHL including histologically confirmed FL, MZL, and mantle cell lymphoma (MCL). Pts received capivasertib 480 mg orally twice daily using an intermittent schedule of 4 days on/3 days off in 28-day cycles until disease progression or unacceptable toxicity. Response was assessed by investigators based on the modified Lugano Classification lymphoma response criteria (Cheson, et al. JCO 2014). Baseline PTEN status and genomics will be correlated with clinical efficacy. Results: At data cut off (DCO; December 21, 2022), 15 pts with R/R B-NHL had been treated (histology: FL [n=11], MZL [n=2], MCL [n=2]). Pts had a median age of 55 (range 40–87) years and had received a median of 3 prior lines of therapy (2–5), including prior PI3Ki (n=6), and autologous stem cell transplant (n=1). Six (40%) pts were refractory to their most recent therapy. Median follow-up for dosed pts was 5 (range 1–11) months. Treatment was ongoing in 9 (60%) pts. 11/13 pts with FL or MZL were evaluable for efficacy (FL 10/11, MZL 1/2). ORR was 54%; 8% of pts had a CR, 46% had a PR, 23% had SD, and 8% had PD. No response data are available for the MCL cohort because both pts were not evaluable at DCO. Grade ≥3 TEAEs occurred in 3 pts: COVID-19, QT prolongation, and rash; no grade ≥3 infections other than COVID-19 were reported. No immune-mediated adverse events or treatment-related deaths occurred. One (7%) pt discontinued due to TEAE (grade 3 QT prolongation). The most common TEAEs (≥25% of patients) were diarrhea (93%), fatigue (27%), and nausea (27%). Diarrhea events were all grade 1 (57%) or 2 (43%) and mainly occurred on dosing days. Summary/Conclusion: Capivasertib demonstrated single-agent activity and a manageable safety profile in pts with heavily pretreated R/R FL. Notably, no immune-mediated events and no treatment-related deaths were observed. Capivasertib has the potential to be an alternative therapeutic option for pts with R/R B-NHL, with a non-overlapping safety profile compared to currently available PI3Ki. Keywords: Akt, Kinase inhibitor, Non-Hodgkin’s lymphoma